[Frontiers in Bioscience S2, 112-116, January 1, 2010]

Dilated cardiomyopathy: etio-morphologic investigation

Brian Chiu, Consolato Sergi

Department of Laboratory Medicine and , University of Alberta Hospital, University of Alberta, Edmonton, Alberta, Canada

TABLE OF CONTENTS

1. Abstract 2. Introduction 3. Etiology 4. The Edmonton Experience 4.1.Clinicals 4.2.Gross Morphology 4.3. 4.4.Ultrastructural Morphology 5. Conclusions 6. References

1. ABSTRACT 2. INTRODUCTION

The heart is the first organ to form and to The heart is the first organ to form and to function during vertebrate embryogenesis and its correct function during vertebrate embryogenesis and its correct functionality is a “conditio sine qua non” for life. If the functionality is a “conditio sine qua non” for life. If the heart’s pumping power is compromised, chambers dilate heart’s pumping power is compromised, chambers dilate and pulmonary and systemic circulations are altered. and pulmonary and systemic circulations are altered. Dilated cardiomyopathy can appear along a wide spectrum Dilated cardiomyopathy can appear along a wide spectrum of presentations, including no symptoms, subtle symptoms of presentations, including no symptoms, subtle symptoms or heart failure, which occurs when the heart is unable to or heart failure, which occurs when the heart is unable to pump blood to the periphery and oxygenate the organs. pump blood to the periphery and oxygenate the organs. Dilated cardiomyopathy, the most common form of Dilated cardiomyopathy (DCM) is the most common cardiomyopathy, is characterized by a particular complex cardiomyopathy, a group of heart resulting from a of nonspecific pathologic features that do not necessarily primary abnormality in the myocardium (1), accounting for identify the different etiologies. In this study, we review the approximately 55% of the cases. DCM is characterized by etiologic and morphologic features of 86 explanted progressively impaired cardiac contractility and ventricular recipient adult hearts with dilated cardiomyopathy dysfunction. (2) DCM most commonly presents between 18 undergoing orthotopic heart transplantation between 1997 and 50 years of age, and occurs more frequently in men and 2008. than in women. (3) DCM is associated with significant

112 Dilated cardiomyopathy: etio-morphologic investigation

Table 1. Clinical and Morphologic Features in 86 Dilated Cardiomyopathy (UA Hospital, Edmonton Data) No. Cases Age F:M Etiologies/Associated Factors Gross Morphologies (Weight, shape, Histomorphologic Features (percent) (range) ventricular dilation) 10 (12%) 38 8:2 Viral (Viral prodrome/ infections) 468 g (range: 342-640), globular shape, – mixed T- (19-62) biventricular dilation B-cells; fibrosis 1 (0.86%) 27 M WPW syndrome, DCM in mother 447 g, biventricular dilation Inflammation, fibrosis 1 (0.86%) 36 F LGMD 327 g , biventricular dilation Fibrosis 1 (0.86%) 45 F Mucopolysaccharidosis 290 g, RV dilation Fibrosis, myocyte vacuolar degereration 1 (0.86%) 32 F Genetic hemochromatosis 382 g, biventricular dilation, mild Fibrosis, - deposits 1 (0.86%) 59 M Familial (1st degree relative) DCM 446 g, + dilation Fibrosis 1 (0.86%) 21 M Chemotherapy-related for HD) 350 g, dilation, mild Fibrosis 1 (0.86%) 41 F Mixed connective tissue 320 g, LV apex thinned Inflammation, fibrosis, thickened arteriole 2 (1.72%) 22-45 F Peripartum 391 g, biventricular dilation Fibrosis 67 (78%) 51 22:45 Idiopathic 511 g (range: 295-1045) Inflammation – mild, (21-70) globular shape, biventricular dilation, fibrosis hypertrophy, mural thrombus DCM: Dilated Cardiomyopathy, WPW: Wolff-Parkinson-White syndrome, LGMD: Limb-girdle muscular dystrophy, HD: Hodgkin’s disease, RV: Right ventricle, LV: Left ventricle. morbidity and mortality, and is a leading indication for surgery in Western Canada, performing 35-45 orthotopic cardiac transplantation in adults and children worldwide. (3, cardiac transplantations annually. In this study, we 4) summarize the etiology and morphologic features of explanted recipient hearts for DCM. 3. ETIOLOGY 4.1. Clinicals A number of conditions resulting in ventricular Diagnostic criteria for DCM are an ejection dilation and dysfunction, such as ischemic, valvular, fraction of less than 0.45 and/or a fractional shortening of hypertensive, congenital heart diseases and alcoholism less than 25%, and a left ventricular end diastolic should be primarily differentiated from DCM. In the dimension of greater than 112% of the predicted value. By majority of cases, DCM is idiopathic due to lack of an excluding ischemic, valvular, alcoholism (up to 30% of identifiable cause. Familial (genetic) forms of DCM have cases of heart failure can be linked to alcohol drinking in been identified in up to one-third of cases. (5) However, the the Western world), hypertensive and congenital heart true frequency is probably underestimated due to the diseases, we have identified 86 explanted hearts from the diversity of clinical presentation, the variability in Edmonton Database. All individuals are adults (age > 18 penetrance and expression. (6) Over 20 individual disease years) with DCM identified during an 11-year period genes have been identified and screened for mutations in (1997-2008). The patients’ mean age is 48 years affected individuals. (7) The relevance of single nucleotide (range=19-70 years) with F/M ratio of 1:2. Five (6%) polymorphisms of the genome in individuals affected with patients have familial or genetically inherited form of DCM DCM is under intense investigation. Some families have a (including one each of limb-girdle muscular dystrophy, clinical presentation that is characterized by DCM alone, while mucopolysaccharidosis, Wolff-Parkinson-White syndrome, in others, DCM may be associated with additional cardiac genetic hemochromatosis and one familial in which a first manifestations, e.g. conduction-system disorders, valve defects, degree relative, who also showed the disease). One patient or non-cardiac manifestations, such as skeletal myopathy, or was affected with mixed connective tissue disease, one partial lipodystrophy. (8) Possible viral etiologies have been patient developed DCM on adriamycin treatment for implicated in DCM. (1) It is also known that in a minority of Hodgkin’s disease), two patients with peripartum history, cases, toxic, metabolic, or immunologic causes may play a 10 (12%) with viral prodrome or of previous viral predisposing or triggering role. (9) A high prevalence (67.4%) infections, and the remaining 67 (78%) cases are idiopathic of viral genomes has been found in the heart of 245 with unknown etiologies. (Table 1) consecutive DCM patients in a recent survey investigating a broad panel of viruses. (10) The frequent detection of viral 4.2. Gross morphology genomes in human DCM hearts strongly suggests that viral Hearts of patients with dilated cardiomyopathy infections may represent an important contributing factor in the showed a huge increase in mass with the mean heart weight of DCM. Interestingly, even a small cardiac virus of 491 g (range: 228 – 1045 g). The heart shape was load during chronic latent infections is able to sustain usually globular with dilation of all chambers and the significant viral transcriptional activity over long periods of disappearance of a proper apex (apical rounding known as time, resulting in slow and progressive deterioration of cardiac Roman arch). Four chamber or biventricular dilation was function. (11). seen in 73 (85%) of our cases. The epicardium was usually smooth and the coronary arteries appeared stretched, but 4. THE EDMONTON EXPERIENCE did not show high-grade atherosclerosis. The myocardium was flabby and the ventricular wall collapsed on section. The University of Alberta Hospital in Edmonton, Cardiac hypertrophy was shown by both weight increase Canada is the leading tertiary care centre for cardiovascular and eccentric hypertrophy, although this finding was not

113 Dilated cardiomyopathy: etio-morphologic investigation

common finding. In up to 10 (12%) cases, mural thrombi formed during the terminal stages of the disease. These latter findings are due to the reduced ejection fraction (a pattern of the cardiac apex that is also called: the change from caput vivum to caput mortuum). There were no primary valvular alterations, but rolling of leaflet edges may be seen in the mitral valves as a result of cardiac remodeling, ventricular dilation, and functional regurgitation.

4.3. Histopathology DCM is characterized by a particular complex of nonspecific histopathologic features that are common to most end-stage cardiac conditions, and do not necessarily identify the different etiologies causing DCM. All our cases showed this complex of histopathologic features. It is important to emphasize that DCM change involves all myocardial components, including myocytes, interstitium, small vessels, and endocardium. The myocardium is both hypertrophied and dilated. Myocytes may appear thickened with hyperchromatic and often bizarrely shaped nuclei. Moreover, thinning, waving, and side-to-side slippage of myocytes, characteristics associated with dilation, are seen interspersed between the hypertrophied myocytes. Enlarged, rectangular and hyperchromatic nucleus may be transversely arranged and occupies the entire cross- sectional area of the attenuated myocytes. Loss of intracellular myofibrils may result in hydropic changes of the myocytes, which are often localized in the subendocardial layer and ranges from perinuclear halo to a pattern of colliquative myocytolysis.

Areas of myocyte death was evident in all our DCM hearts by the presence of interstitial and perivascular fibrosis predominantly, whereas replacement and Figure 1. Peripartum DCM: Large organized thrombus endocardial fibrosis were seen focally. In four cases (5%), adherent to endocardium, H&E, 40x. Peripartum DCM: fibroadipose tissue replacement was significantly more Myocyte hypertrophy, nucleomegaly (arrow), mild prominent in the right ventricle, reminiscent of that seen in interstitial fibrosis, lymphocytic infiltrate (double arrow), arrhythmogenic right ventricular (ARVD). H&E, 400x. Hemochromatosis DCM: Myocyte Significant iron overload with intramyocellular iron hypertrophy, mild nucleomegaly, cytoplasmic iron deposits deposition resulting in myocellular degeneration indicative in myocytes (arrow) and reticuloendothelial cells, H&E, of hemochromatosis was seen in one patient. Inflammatory 400x. Hemochromatosis DCM: Abundant iron in myocytes. cellular infiltrates were seen in 25 cases (29%) ranging Perl’s Prussian blue, 400x. Mixed connective tissue disease from a single microscopic focus to patchily and often DCM: Thickened arteriole, interstitial fibrosis and around areas of fibrosis. The inflammatory cells were lymphocytic infiltrate (double arrow), H&E, 400x. Viral composed almost exclusively of lymphocytes of mixed T- Myocarditis DCM: Myocyte hypertrophy, slight and B-cells by immunophenotyping studies. These findings nucleomegaly, myocytolysis (arrow), lymphocytic infiltrate were consistent with an activated immunologic process (double arrow), H&E, 400x. Mucopolysaccharidosis DCM: within the myocardium in DCM. (12) (Figure 1) Slight nucleomegaly, myocyte vacuolar degeneration (arrow), interstitial fibroadipose tissue replacement (double A disordered arrangement of desmin intermediate arrow), H&E, 400x. Mucopolysaccharidosis DCM: filaments also characterizes a myocellular derangement of Ultrastructural: Myocyte degeneration, myofibrils the myocytes as detected by . In separated by myelin figures (arrows), consistent with MPS particular, an immunohistochemical procedure may also be accumulation. needed to demonstrate an abnormal type I/type III fibrillar collagen ratio. In a recent study, atrial natriuretic protein evident in the majority of our cases because of ventricular (ANP) and CD34 (an endothelial and stem cell marker) chamber dilation. The mean thickness of the right ventricle were significantly over-expressed in IDCM compared to wall was 0.35 cm (range: 0.2 to 0.7), whilst that of the left normal heart (NH). Patients with a difference of more than ventricle 1.4 cm (range: 0.75 to 1.6). The extreme thinning 20 myocardial fibers in the compared expression between may be seen at left ventricle apex. Fibrosis was frequently CD34 and troponin T were associated with a quite less found, but very variable with replacement fibrosis ranging favorable survival although the difference was not from minimal to larger areas. Endocardial fibrosis was a significant (13). The increase in ANP positive cells in

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IDCM could be a consequence of neuro-hormonal 6. REFERENCES activation due to a decline of the impaired myocyte contractility. Further, since it was already shown that ANP 1. P. Richardson, W. McKenna, M. Bristow, B. Maisch, B. could be important in the control of vascular remodeling, Mautner, J. O'Connell, E. Olsen, G. Thiene, J. Goodwin, I. we postulated that the increment of CD34 positive cells Gyarfas, I. Martin, P. Nordet: Report of the 1995 World could be functionally correlated to the increase of ANP Health Organization/International Society and Federation production. Differential expression of CD34 and troponin T of Cardiology task force on the definition and classification might be used for future studies to evaluate their prognostic of cardiomyopathy. Circulation. 93:841 (1996) value. (13) 2. Frederick Schoen: The Heart. In: Robbins and Cotran 4.4. Ultrastructural morphology Pathological Basis of Disease. Eds: Vinay Kumar, Abul K. 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Key Words: Cardiomyopathies, Dilated Cardiomyopathy, Etiology, Genetic, Environment, Review

Send correspondence to: Brian Chiu, Department of Lab. Medicine and Pathology, 8440 – 112 Street, WC Mackenzie Center-UA Hospital, University of Alberta, Edmonton, Alberta, Canada. T6G 2B7, Tel: 1-780-407-6959, Fax: 1-780-407-3009; E-mail: [email protected] http://www.bioscience.org/current/vol2S.htm

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